Down Syndrome: Current Perspectives [1 ed.] 9781909962484, 9781909962477

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Clinics in Developmental Medicine

Down SynDrome: Current PerSPeCtiveS

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Clinics in Developmental Medicine

Down Syndrome Current Perspectives Edited by riCharD w newton

Royal Manchester Children’s Hospital Manchester UK Shiela Puri

University of Leeds UK liz marDer

Nottingham Children’s Hospital Nottingham University Hospitals NHS Trust Nottingham UK

2015 Mac Keith Press

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© 2015 Mac Keith Press 6 Market Road, London, N7 9PW Editor: Hilary M. Hart Managing Director: Ann-Marie Halligan Commissioning and Production Editor: Udoka Ohuonu Project Management: Lumina Datamatics The views and opinions expressed herein are those of the authors and do not necessarily represent those of the publisher. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written consent of the copyright holder or the publisher. First published in this edition in 2015 British Library Cataloguing-in-Publication data A catalogue record for this book is available from the British Library

Cover: Main image, Michael Newton - ‘Thumbs up to life’. Top circle, Billie-Jo Bailey at school, © Richard Bailey. Middle circle, Prisca Byera, courtesy of Mariana Melo Lima (www.marianamelolima.com). Bottom circle, Feet typical of Down syndrome. Photograph by Katy Francis of her own feet. Used with permission. ISBN: 978-1-909962-47-7 Typeset by Lumina Datamatics, Chennai, India Printed by Berforts, Information Press, Eynsham, Oxford, UK Mac Keith Press is supported by Scope

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DEDICATION

We would like to dedicate this book to: Our families . . . Davina, Aiysha, Rajiv, Pooja and Sunil Surinder, Joe and Hannah Judith, Sarah, Mike, Jenny, Chris and Will . . . for their love and giving us the opportunity and encouragement to complete this work; to parents everywhere as they help their children with Down syndrome reach their potential; to people working in medicine, education and social care who offer those families support in the light of current knowledge; and to the Down’s Syndrome Association and like organizations everywhere for their continuing important work.

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CONTENTS AUTHORS’ APPOINTMENTS FOREWORD

xiii

ACKNOWLEDGEMENTS

xv

PROLOGUE

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ix

xvii

1

INTRODUCTION

1

2

ADVANCES IN MOLECULAR GENETICS

3

3

ANTENATAL DIAGNOSIS: GIVING THE NEWS

13

4

LIFE WITH AND FOR A PERSON WITH DOWN SYNDROME

23

5

HEARING ISSUES

70

6

VISION AND EYE DISORDERS

77

7

IMMUNE FUNCTION, INFECTION AND AUTOIMMUNITY

88

8

CARDIOVASCULAR DISEASE

98

9

RESPIRATORY DISEASE

111

10 GROWTH

127

11 ENDOCRINE DISORDERS

137

12 HAEMATOLOGICAL DISORDERS

155

13 GASTROINTESTINAL DISORDERS

165

14 RENAL AND URINARY TRACT ABNORMALITIES

181

15 MUSCULOSKELETAL MANIFESTATIONS

187

16 DERMATOLOGICAL MANIFESTATIONS

210

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17 ORAL AND DENTAL HEALTH

229

18 NEUROPSYCHIATRY OF DOWN SYNDROME

238

PART 1: NEUROLOGICAL DISORDERS

238

PART 2: DEVELOPMENTAL, PSYCHOLOGICAL AND PSYCHIATRIC FUNCTION

248

PART 3: MENTAL HEALTH AND DEMENTIA IN ADULTS WITH DOWN SYNDROME

258

19 INTERVENTION AND ALTERNATIVE THERAPIES: MEDICINE, MYTH AND MAGICAL BELIEF

270

20 PERSPECTIVES

279

APPENDIX 1

MEDICAL SURVEILLANCE AND GUIDELINES

281

APPENDIX 2

SOME ADDITIONAL RESOURCES FOR FAMILIES

284

INDEX

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AUTHORS’ APPOINTMENTS

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Sarah Almond

Locum Consultant Paediatric Surgeon, Royal Manchester Children's Hospital, UK

Tiina Annus

Research Assistant, Cambridge Intellectual and Developmental Disabilites Research Group, Department of Psychiatry, University of Cambridge, UK

Peter Arkwright

Consultant Paediatric Immunologist, Department of Immunology, Royal Manchester Children’s Hospital, UK

Gillian Bird

Training Services Manager, Down's Syndrome Association, Teddington, UK

Lesley Black

Down's Syndrome Association, Teddington, UK

Arjan Bouman

Clinical Geneticist in Training, Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, The Netherlands

Pat Charleton

Chairman DSMIG (UK and Ireland); Associate Specialist Paediatrician, Department of Community Child Health, Royal Aberdeen Children's Hospital, Aberdeen, UK

Natali Chung

Consultant Cardiologist, Adult Congenital Heart Disease, Guy’s and St Thomas’ Hospital NHS, Foundation Trust, London, UK

Sheila M. Clark

Consultant Dermatologist, Leeds Teaching and Mid Yorkshire Teaching Hospitals NHS Trust, Member of the British Association of Dermatologists and the British Society for Paediatric Dermatology, UK

Jennifer Dennis

Retired Paediatrician, and Specialist Advisor to Down Syndrome Medical Interest Group (UK and Ireland), Oxford, UK

Malcolm Donaldson

Honorary Senior Research Fellow Glasgow University, UK

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Down Syndrome: Current Perspectives Hazel Evans

Consultant Respiratory Paediatrician, Southampton General Hospital, Tremona Road, Southampton, UK

Janet GardnerMedwin

ARC Clinical Senior in Paediatric Rheumatology Royal Hospital for Sick Children Glasgow, UK

Peter Gillett

Consultant Paediatric Gastroenterologist, Royal Hospital for Sick Children, Edinburgh, UK

Christine Hardie

Associate Specialist in Community Paediatrics, Ashurst Child and Family Health Centre, Southampton, UK

Raoul Hennekam

Professor of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands

Sheila Heslam

Services Director, Down's Syndrome Association, Teddington, UK

Hilary Hoey

Emeritus Professor of Paediatrics University of Dublin, Trinity College, and Consultant Paediatric Endocrinologist, National Children’s Hospital, Dublin; Dean of the Faculty of Paediatrics and Vice President of the Royal College of Physicians of Ireland, Dublin, Ireland

Anthony Holland

Health Foundation Chair in Learning Disabilities, Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, UK

Patricia D Jackson

Paediatrician, Honorary Senior Fellow, University of Edinburgh, UK

Beki James

Consultant Paediatric Haematologist, Leeds Children's Hospital, Leeds General Infirmary, UK

Kath Leyland

Consultant Community Paediatrician, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK

Liz Marder

Consultant Paediatrician and Pathway Lead Clinician for Children and Young People, Nottingham Children’s Hospital, Nottingham University Hospitals NHS Trust, UK

Lou Marsden

Down's Syndrome Association, Teddington, UK x

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Authors’ Appointments Claire McCall

Associate Specialist in Paediatrics, Nottingham Children’s Hospital, Nottingham University Hospitals NHS Trust, UK

Liz McDermott

Consultant Immunologist, Nottingham University Hospitals NHS Trust, UK

Marian McGowan

Consultant Paediatrician, Child Development Centre, St George's Hospital London, London, UK

Emma McNeill

Clinical Fellow in Otolaryngology, Freeman Hospital, Newcastle-upon-Tyne, UK

Stuart Mills

Information Officer, Down's Syndrome Association, Teddington, UK

Joan Morris

Director of the National Down Syndrome Cytogenetic Register, Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine; the London School of Medicine and Dentistry, Queen Mary University of London, UK

Richard Newton

Honorary Consultant Paediatric Neurologist, Royal Manchester Children’s Hospital, UK

June Nunn

Professor of Special Care Dentistry and Dean of the School of Dental Science, Trinity College, Dublin, Ireland

Emma Pascall

Department of Congenital Heart Disease, Bristol Royal Hospital for Children, Bristol, UK

Katy Pike

Clinical Lecturer, University of Southampton and NIHR Southampton Research Unit, University Hospital Southampton NHS Foundation Trust, UK

Rajiv Puri

Consultant Urological Surgeon, Yorkshire Clinic, Bradford, UK

Sheila Puri

Consultant Paediatrician in Community Child Health, Children and Family Services, NHS Leeds Community Healthcare, St James's University Hospital, Child Development Centre, Leeds, UK

Vanda Ridley

Information Services Manager, Down's Syndrome Association, Teddington, UK xi

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Down Syndrome: Current Perspectives Laura Savage

Dermatology Specialist Registrar, Leeds Centre for Dermatology, Chapel Allerton Hospital, Chapeltown Road, Leeds, UK

Patrick Sheehan

Consultant & Honorary Senior Lecturer in Paediatric Otolaryngology, St Georges Hospital and Medical School, London, UK

Sally Shott

Professor, Department of Otolaryngology Head and Neck Surgery, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA

Fiona Straw

Consultant Paediatrician, Nottingham Children’s Hospital, Nottingham University Hospitals NHS Trust, UK

Sally Tennant

Consultant Paediatric Orthopaedic Surgeon, Royal National Orthopaedic Hospital and St Mary's Hospital Paddington, London, UK

Maureen Todd

Senior Research Nurse, Glasgow Clinical Research Facility, Western Infirmary, Glasgow; University of Glasgow, UK

Robert Tulloh

Consultant in Paediatric Cardiology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, UK

Jeremy Turk

Professor of Developmental Psychiatry, Institute of Psychiatry, King's College, University of London, and Consultant Child & Adolescent Psychiatrist, South London & Maudsley NHS Foundation Trust, London UK

Liam Reese Wilson

Research Assistant, Cambridge Intellectual and Developmental Disabilites Research Group, Department of Psychiatry, University of Cambridge, UK

Maggie Woodhouse

Senior Lecturer and Optometrist, School of Optometry & Vision Sciences Cardiff University, Maindy Road, Cardiff, UK

xii

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FOREWORD The prospects for individuals born with Down syndrome today are better than ever and many should expect to live long, healthy lives filled with the experiences and challenges most of us take for granted. Of course, this has not always been the case. Many individuals born with Down syndrome within living memory were denied treatment for remediable conditions simply on the basis of their genetic condition. I recall the teenager with severe pulmonary hypertension as a result of an untreated cardiac lesion and the cardiologist’s letter justifying the decision not to treat as ‘being in his best interest’ in some way. Thankfully, such situations are no longer acceptable in contemporary medicine, but the spectre of previous discrimination and medical patriarchy hangs over and shames our profession. Therefore, as both a paediatrician caring for children with Down syndrome and as the parent of a young person with Down syndrome, I am delighted to welcome this excellent book, which provides a comprehensive guide to the delivery of healthcare for children and young people with Down syndrome, within the context of promoting health and well-being. The book covers the fascinating genetic aspects of the syndrome (Why do some children have cardiac defects while others do not, yet all have Down syndrome?) followed by consideration of the perinatal aspects of diagnosis, counselling and management. We are reminded how to impart a diagnosis and pitfalls to avoid. Memories of the ward round with the consultant reciting a list of possible complications to the newborn infant’s stunned parents return to make me cringe even now. The book includes a system-by-system guide, using case examples to illustrate important topics, with key learning points highlighted for easy reference. The book contains practical advice on the management of both common and rare complications: when do you test thyroid antibodies and which ones do you request? Is a cervical spine X-ray needed before the child takes part in trampolining classes? What is the long-term outcome? How likely is someone with Down syndrome to become independent and what is the current life expectancy?—all essential information for clinicians guiding parents. The phenomenon of diagnostic overshadowing (the attribution of symptoms to Down syndrome per se rather than consideration of either known associations or unrelated conditions) is highlighted and this should prompt reflection of one’s own practice and assumptions. Importantly, the book contains a chapter from the Down’s Syndrome Association of the UK outlining the practical day-to-day issues that families may experience and this will be an invaluable source of information for clinicians. Having Down syndrome does not make an individual unhealthy, but there are particular conditions that are seen more commonly and clinicians need to be aware of the best evidence-based management. This comprehensive overview condenses that knowledge into one source.

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Down Syndrome: Current Perspectives It is written with authority and credibility by experts in the field. I predict it will become the main reference text for clinicians working with children with Down syndrome. I hope it will spearhead an advance in the quality and consistency of care delivered to children. Good health is the foundation of participation, fulfilment and achievement of full potential. This book is the clinicians’ guide to helping individuals with Down syndrome achieve those ideals. Dr Neil A Harrower Consultant Paediatrician, Ryegate Children’s Centre, Sheffield Children’s NHS Foundation Trust; and Honorary Senior Lecturer, University of Sheffield, UK.

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ACKNOWLEDGEMENTS A project of this size requires help and support from many quarters. Knowledge about Down syndrome is advancing very fast. We had to ensure up-to-date advice on molecular genetics, clinical practice and then, of course, the application of science into practice. We are therefore indebted to all our authors and to Carol Boys, Chief Executive of the Down’s Syndrome Association for mobilizing resources so that the useful perspective of the lives of people with Down syndrome of all ages could be depicted in Chapter 4. This allows practitioners important insight into the context in which we apply our medical knowledge. All members of the Down Syndrome Medical Interest Group (DSMIG) UK and Ireland deserve mention for presentations and discussion over the years that have informed many of the ideas in this book. We should give special mention to Drs Christine Jenkins, Rebecca Ferris and Jill Ellis who laid down important groundwork to enable the chapters on Dermatology, Respiratory disorders and Intervention to take off; and Joyce Judson and Lynn Nixon, Information Officers at the Child Development Centre, City Hospital Campus, Nottingham, supported many authors by providing background information. We are grateful to Mr Antonino Morabito and Dr Nick Webb for guidance on the chapters on gastroenterology and renal abnormalities. Gratitude should also be paid to all the children with Down syndrome and their families for all they have taught us and the motivation for writing this book. We should mention Dr Jennifer Dennis who taught many of us much about working with families with children with Down syndrome and whose painstaking work was a foundation for the DSMIG. We would like to thank scientists everywhere who through their painstaking work continue to establish the facts about Down syndrome and dispense with unhelpful myths. In this context, special acknowledgement needs to be given to our friend and colleague Professor Cliff Cunningham who sadly died at the advent of this project. He advised on its shape and a number of central themes. His experience, wisdom, scholarship and foresight, along with the establishment of the Manchester cohort, laid a solid foundation for applied psychology and medical research in the area. He was a friend to many families. His keen sense of fun is greatly missed. Finally, we would like to thank Mac Keith Press for commissioning the project and in particular Ann-Marie Halligan and Hilary Hart for help, guidance and support. Richard Newton, Shiela Puri and Liz Marder December 2014

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PROLOGUE My 17-year-old son was diagnosed with PH+ ALL in November 2012. When any parent hears those words, it is normal for a rampage of fear to run through them. For me, the fear was complicated and compounded by the fact my son has Down syndrome. Along with the normal fears of seeing your child sick, suffering, in pain, or God forbid, not surviving at all, I have the extra fears. Will the doctors treat my son? Seventeen years ago, I had to fight for life-saving cardiac surgery to be done. Would I have to fight again? Would his human rights be respected, acknowledged or even recognized? What will the doctors and nurses think of my son’s behaviour? Being completely nonverbal, he can act out his fears, anger or frustrations with behaviours not commonly seen on a teen oncology ward. Those same behaviours can be an indication of pain or sickness. I would hate for my son to be judged as a naughty, unmanageable, learning disabled teen, when all he is trying to convey is that he feels sick or is in pain. I fear telling people in case I hear the dreaded ‘maybe it is for the best’. The best for whom? Certainly not the best for my son, definitely not for his sister or I nor the best for his friends or anyone who loves him. I fear seeing the look of the others on the ward (patients, their parents, family or visitors) looking at us as if we do not quite belong. None of the other parents can relate to us, as we share stories over a cuppa because my son is different. It is as if we are a piece of a puzzle that just does not quite fit anywhere. I fear that his extra chromosome might breakdown his chemotherapy so differently. I fear not being able to explain to my son about his own illness. He looks at me with tear-filled almond eyes pleading, ‘Why are you doing this to me?’ I fear the heavy burden of having to make life choices for him. I hope and pray I am making choices he wants and choices not just for my own selfish reasons. I fear people looking at my son and only seeing a waste of resources. No, my son may never pay taxes, but he can and does contribute to society. He educates people, he teaches love and acceptance, he also spreads laughter and joy. But mostly, I fear they will not see the Person, the Person we love very dearly. xvii

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Down Syndrome: Current Perspectives Thankfully I have not had to face any of those fears here on Ward 33. My son has been welcomed, accepted and yes, even loved. I have every confidence that his consultant and her amazing staff have nothing but my son’s and family’s best interest at heart. They are, rightly, along with us, for us. Thank you all eternally.

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1 INTRODUCTION

The scene is a school leavers’ assembly at a 1500-pupil comprehensive school. The assembled pupils have a wide range of prospects: ranging from aspirant lawyers and teachers to those with antisocial behaviour orders. One of them was asked to make a short speech. The 16-yearold begins hesitantly but the 300 gathered listen respectfully. The address is short, clear and poignant, ‘I would like to thank everybody for helping me and being my friend’. There is rapturous applause. The boy leaves the stage, a little self-consciously but with a look of satisfaction. The gathering offers genuine warmth and delight in response to the lad’s words. The young person in question has Down syndrome and has just passed through mainstream education. One teacher remarked that this pupil had offered more to this school than they had been able to give him. This reflects a sea change in societal attitude to children with Down syndrome over the past 40 years (only after the 1970 Education Act [UK] where children with intellectual disability entitled to an education at all). By the 1980s, ‘Mongol’ was only just leaving common parlance and a prejudicial view often entered medical decision-making processes: suboptimal treatments were reported for heart disease and leukaemia. Fortunately this has changed, reflecting a view that young people with Down syndrome have prospects, can contribute to society, and deserve respect, love and emotional support along with access to appropriate medical care. Down syndrome is not a medical condition but represents a common recognizable variation of the human form created through a random biological event. Nonetheless, as we will see, people with Down syndrome present with many common medical conditions and some that are more specific to the condition. Doctors have an important part to play in the lives of the people concerned. They help parents readjust to a new set of expectations following the birth of an affected child. They can help with the early identification and treatment of conditions attendant on the syndrome. We will illustrate through a number of case scenarios that, unfortunately, too often medical symptoms are attributed to the ‘syndrome’. This is termed ‘diagnostic overshadowing’ and results in a delay in the delivery of appropriate medical care. We hope this book will strengthen the knowledge of doctors and other health professionals who have this responsibility. Our book incorporates anecdotes and experiences, some good some bad, of service providers and users which illustrate good and bad practice, and missed opportunities. We hope these vignettes will help the readers reflect on their own attitudes and practice in our shared constant quest for professional development and improvement. We begin with an overview of our current knowledge of the biology of Down syndrome. It is followed by an important contribution from the UK Down’s Syndrome Association 1

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Down Syndrome: Current Perspectives which explores the lives, experiences and at times frustrations of service users and how we might improve our practice. We then take a systematic approach to Down syndrome and its attendant medical problems—the biology, presentation and diagnostic formulations; and how we might intervene in a timely fashion. Presentations can be different in Down syndrome; the important thing is to recognize this so that opportunities to help are not missed. An underlying theme is how we might initially set the scene for a loving and nurturing environment at home and then develop this into opportunity and encouragement outside the home as the children get older. We believe professionals will best be able to fulfil their part in this task by first examining and reflecting on their own views of disability in general and Down syndrome in particular. An increased understanding of Down syndrome should allow us as professionals to support the person at the centre and their families; and to present information and interventions clearly and positively enabling them to lead a fulfilling life.

2

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2 ADVANCES IN MOLECULAR GENETICS Arjan Bouman and Raoul Hennekam

Introduction In 1959, Lejeune et al. (Lejeune et al. 1959) identified the cause of Down syndrome as an additional chromosome 21 in the human cell (since we have learnt the discovery was actually made by his colleague Dr Marthe Gautier [Harper 2006]). The trisomy of chromosome 21 influences almost every body tissue, resulting in a broad and distinct phenotype. Despite many years of intensive research, the mechanisms involved remain unclear. Everyone with Down syndrome has an intellectual disability (Nadel 2003). From the fourth decade of life, they have a significantly increased risk of developing Alzheimer disease (Zigman et al. 2008). Alterations in neurogenesis, neuronal differentiation, myelination, dendritogenesis, synaptogenesis and other mechanisms are suggested to underlie the cognitive impairment. However, the exact mechanisms responsible remain little understood (Rachidi and Lopes 2010). It is assumed that chromosome 21 gene overdosage plays a major role in Down syndrome-related neurodegeneration. Yet, the wide range of variation in the degree of intellectual disability in Down syndrome is difficult to explain with a gene overdose hypothesis. This chapter will explore our current knowledge of the molecular mechanisms and pathways which contribute to the phenotypic features and suggest areas for future research. This growth in understanding should eventually serve as a basis to develop personalized medicine strategies for each individual with Down syndrome. To help understand this chapter it may be helpful to look at Box 2.1 that shows the relevant biological terms. General hypotheses It is hypothesized that there are two pathophysiological mechanisms which may cause the Down syndrome phenotype (see Fig 2). Both hypotheses involve several mechanisms which may be acting through altered gene transcription, tissue-specific gene transcription, genetic interaction, DNA methylation, altered microRNA activity, posttranscriptional mechanisms (e.g. RNA editing) and altered chromosome territories. Many more mechanisms, currently undetected, may be present. Neither hypothesis rules out the other, and they may well influence one another. For example, overexpression of some of the chromosome 21 genes may directly influence the phenotype, but it may also disturb genetic cell homeostasis in a more general way. 3

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Down Syndrome: Current Perspectives BOX 2.1 A synopsis of molecular biology terms The genome is the genetic material of any organism, which in humans is encoded in DNA. The essence of life is that Deoxyribonucleic acid (DNA) can make Ribonucleic acid (RNA) which then assembles protein. Messenger RNA (mRNA) is a large family of molecules that convey genetic information from DNA to ribosomes where protein is assembled. mRNA specifies the amino acid sequence of the protein. An exon is a sequence of nucleotides encoded by a gene that remains in the final RNA product of that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and its RNA transcripts. Introns are regions inside a gene and the corresponding RNA transcript sequence not included in the final protein gene product. RNA splicing is the process by which introns are removed and exons are joined in order to make mature messenger RNA. The exome is the part of the genome formed by exons, the sequences which when transcribed remain within the final RNA sequence after introns are removed by RNA splicing. The transcriptome is the set of all RNA molecules, including messenger RNA, ribosomal RNA, transfer RNA and other non-coding RNA produced in one cell or a population of cells, i.e., all the different forms of RNA required in the process of transcribing DNA into protein assembly. The proteome is the entire set of proteins expressed by the genome, be it in a cell or specific tissue at a given time. The metabolome is the complete set of small molecules found in a biological sample, be it a cell, organelle, organ or tissue. It would exclude macromolecules such as proteins, DNA or RNA but includes metabolites and other molecules such as drugs. The interactome is the whole set of molecular interactions in a particular cell. It may refer to physical interactions among molecules or indirect interactions among genes.

Hypothesis 1: Dosage effect The unifying simplified description of this theory is that a 1.5-fold increase of dosage results in a 1.5-fold increase of chromosome 21 gene expression causing (specific aspects of) the Down syndrome phenotype (Korenberg et al. 1990, Patterson 2007, Rachidi and Lopes 2010). Several studies on mRNA expression in Down syndrome have shown that a significant number of genes on chromosome 21 are overexpressed to 150% (Mao et al. 2003, Prandini et al. 2007). This observation was confirmed by Aït Yahya-Graison et al. (2007) who demonstrated that 29% of chromosome 21 transcripts are overexpressed in Down syndrome. The other 71% of transcripts are either compensated (e.g. with an antisense transcript) or highly variable. Lockstone et al. (2007) found a similar 27% of chromosome 21 genes are upregulated in the adult brain with Down syndrome. Korbel et al. (2009) constructed a phenotype map for various specific manifestations of Down syndrome by using clinical information from 30 individuals carrying a segmental trisomy of chromosome 21. This map identified candidate genes on chromosome 21 that may be involved in pathways causing particular phenotypic Down syndrome features such as Hirschsprung disease, leukaemia, Alzheimer disease and intellectual disability. It is assumed that these specific manifestations can be explained by an elevated expression of particular chromosome 21 genes. The dosage effect hypothesis does not describe specific genes, subsets of genes or 4

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Advances in Molecular Genetics molecular pathways which are responsible for specific Down syndrome features. Down syndrome mouse model experiments show that a trisomy of the Down syndrome critical region (DSCR) can explain some, but not all, phenotypic features of Down syndrome (Olson et al. 2007). The duplication of the DSCR is associated with many Down syndrome features (e.g. morphologic characteristics, intellectual disability) but does not explain the full Down syndrome phenotype. In addition, expression levels of chromosome 21 genes can differ between tissues (Li et al. 2006). Selected geneS located on chromoSome 21 In 2011, GENCODE (release 8) identified 696 genes on chromosome 21. Proteins encoded by these genes are involved in 636 different biological processes, have 304 different molecular functions and are present in 163 cellular components (Letourneau and Antonarakis 2012). The specific function of about 50% of the genes lying on chromosome 21 remains uncertain (Kahlem 2006). The various candidate genes which could underlie parts of the neurological phenotype in Down syndrome can be listed in the following subgroups: • Genes involved in brain development (neurogenesis, neuronal differentiation, myelinization and synaptogenesis) • Genes involved in neuronal cell–cell communication • Genes involved in metabolic processes influencing the brain. The neurological Down syndrome phenotype cannot be explained by changes determined within a single pathway described by a gene from any of the subgroups listed above, but is likely to involve a complex interaction with disturbed regulation of several pathways. Fully understanding and dissecting these complex molecular networks requires full insight into the exome, transcriptome, proteome, metabolome, interactome, synergistic effects and probably more besides. Gaining insight in these molecular processes will give us the tools needed to identify candidate genes involved in Down syndrome aetiology. As genes within the DSCR play an important role in Down syndrome pathogenesis but cannot fully explain the phenotype, the focus should not be limited only to the chromosome 21 DSCR but rather should include all interactive aspects of a genome-wide view. As the biological function of half of the genes located on chromosome 21 remains unknown (Kahlem 2006), it may be that several genes of great importance for producing the Down syndrome phenotype remain unrecognized as such. Further studies of the function of these genes are clearly important for our understanding. Selective knocking out of such genes in animal models and studying phenotypes in individuals who harbour variants in one of these genes are first-line studies needed for this. Amyloid Precursor Protein and Beta-Site Amyloid Beta A4 Precursor Protein-Cleaving Enzyme 2 Chromosome 21 harbours at least two genes which are involved in the development of Alzheimer disease: amyloid precursor protein (APP) and beta-site amyloid beta A4 precursor protein-cleaving enzyme 2 (BACE2). APP serves as a substrate for amyloid b-peptide (Aß), 5

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Down Syndrome: Current Perspectives a pathogenic amino acid peptide which can precipitate in extracellular plaques in the brain (see also Chapter 18c). Widespread Aß deposition is the hallmark feature in Alzheimer disease resulting in profound neurodegeneration. Brains of aged individuals with Down syndrome show approximately a 1.5-fold increase of APP mRNA levels compared with those of typically developed individuals (Oyama et al. 1994). Rovelet-Lecrux et al. (2006) reported on five families with early-onset Alzheimer disease caused by an isolated duplication of the APP locus (ranging from 0.58Mb to 6.37Mb). This study demonstrated that trisomy of APP can explain the neuropathology associated with Alzheimer disease in Down syndrome, but that it is not sufficient to cause the full Down syndrome phenotype. In addition, Salehi et al. (2006) demonstrated in a Down syndrome mouse model (Ts65Dn) that APP overexpression can cause degeneration of basal forebrain cholinergic neurons. The second gene of interest is BACE2, an aspartyl protease which has a 65% homology to BACE1. In the brain, b-Secretase (BACE1) is the rate-limiting protease in the generation of Ab peptide from APP. BACE1 activity is further increased in Alzheimer disease (Webb and Murphy 2012). Unlike BACE1, BACE2 is more highly expressed in peripheral tissues, but also to some extent in the brain. Both its homology to BACE1 and its expression in the brain may pinpoint BACE2 as an important contributing factor in Aß accumulation in the brain (Dominguez et al. 2005). Therefore, both APP and BACE2 seem to contribute to Alzheimer disease neuropathology in Down syndrome but do not, of course, explain the full neurological Down syndrome phenotype. Sorting Nexin 27 Wang et al. (2013) identified a signalling pathway that contributes to the neurological phenotype of Down syndrome. Overexpression of miR-155 (located on the mouse equivalent of human chromosome 21) reduces expression of Sortin Nexin 27 (not located on the mouse equivalent of human chromosome 21). Sorting Nexin 27 (SNX27) is involved in hippocampal and cortical synaptic function. Knock-out mice (SNX27−/−) have severe neuronal deficits in both the hippocampus and cortex. Complete loss of SNX27 in mice results in severe neuronal degeneration and mortality, mainly caused by diminished synaptic glutamate receptor expression. Upregulation of SNX27 in Down syndrome mice (Ts65Dn) rescued synaptic deficits. It was also demonstrated that SNX27 expression is decreased in the cortex of the human Down syndrome brain. These experiments show that the miR-155/ SNX27 pathway is an important player in Down syndrome neuropathogenesis demonstrating the role of the chromosome 21 interactome (Fig. 2.2). Hypothesis 2: Amplified developmental instability This hypothesis indicates that there is a ‘phenotypic instability due to extra genetic information’ or ‘amplified developmental instability’. Thus, dosage imbalances of genes located on chromosome 21 are responsible for a non-specific disturbance of overall genomic regulation and expression. Because of this global balance disruption of gene expression in developmental pathways, normal developmental processes are altered finally resulting in the establishment of the Down syndrome phenotype (Shapiro 1983, Patterson 2007, Rachidi and Lopes 2010). This hypothesis has a significant overlap with the dosage effect hypothesis 6

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Advances in Molecular Genetics

Fig. 2.1. General mechanisms: (1) Dosage effect. This hypothesis describes an upregulation of mRNA transcription of genes located on chromosome 21 to 150%. This 1.5-fold increase in chromosome 21 gene expression results in the Down syndrome phenotype. (2) Amplified developmental instability. This hypothesis describes that dosage imbalances of chromosome 21 genes are responsible for a total (non-specific) disruption of genomic regulation and expression in the cell. This results in a total disturbance of cell homeostasis leading to the Down syndrome phenotype.

Fig. 2.2. Specific mechanisms: (1) Chromosome territories. The coloured areas represent the various chromosome territories within the nucleus. Territory occupied by an extra chromosome 21 causes a displacement in nuclear chromosome territory topography. As a result, expression of particular loci located anywhere in the genome can be influenced. (2) DNA methylation. DNA methylation of a single chromosome is depicted by the addition of CH3 groups. The presence of an extra chromosome 21 causes altered DNA methylation of particular loci which subsequently influences transcription. (3) Chromosome 21 interactome. The extra chromosome 21 causes upregulation in mRNA transcription of a locus on a particular chromosome elsewhere on the genome. Thus, expression of genes not located at the trisomic chromosome but elsewhere in the genome is altered.

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Down Syndrome: Current Perspectives but describes in a broad sense that the presence of extra genetic information will result in a global cellular disturbance. It is known, however, that other autosomal trisomy syndromes (such as trisomy 13 or trisomy 18) can lead to a similar global disturbance of cellular and molecular processes but do not lead to a phenotype similar to Down syndrome. This forms an argument against a significant role for the amplified developmental instability hypothesis; though, of course, it may contribute. Further hypotheses The scope of these two hypotheses (dosage effect and amplified developmental instability) to explain all phenotypic variations seems too limited and non-specific. The effects of the presence of an additional chromosome 21 are likely to be much broader and complex and involve numerous molecular mechanisms (see Fig 2.2). Fortunately, molecular techniques are at present evolving rapidly and will allow us to study such mechanisms. These additional mechanisms are summarized below: altered dna methylation DNA methylation is one of the epigenetic processes. It plays a role in silencing the expression of particular genes without changing the nucleotide sequence of the gene. This is explained by the addition of a methyl group to a DNA strand which can cause altered/ decreased gene expression of this particular DNA segment (i.e. ‘turning off the gene’). This molecular process, therefore, is an important regulator of gene expression (TurekPlewa and Jagodziński 2005). Aberrant DNA methylation can influence the transcription of genes located on the chromosome itself, or loci elsewhere on the genome. DNA methylation can be tissue specific and also age specific. DNA methylation patterns have been studied in Down syndrome by using small cohorts of adults and comparing them to controls (Chango et al. 2006, Kerkel et al. 2010). A difference in DNA methylation and gene expression in adults with Down syndrome was demonstrated. One could hypothesize that the presence of an extra chromosome 21 might alter its DNA methylation or even DNA methylation on other loci or chromosomes throughout the genome. Altered DNA methylation may, therefore, influence transcription of genes located on chromosome 21 and probably elsewhere on the genome as well. Adorno et al. (2013) described ubiquitination as another epigenetic process which could be involved in Down syndrome. They demonstrated in Ts65Dn mice (the Down syndrome mouse model, sometimes referred to as the ‘Downmouse’) that triplication of Usp16, a deubiquitination enzyme, disrupts the epigenetic state of particular genes (such as Cdkn2a). This results in reduced self-renewing capacity of haematopoietic stem cells, which accelerates the ageing process. Also, these mice had a defect in neural progenitor expansion, which can partly be explained by the triplication of Usp16. altered chromoSome 21 interactome In genetics, the interactome describes the interactions between genes located at different positions in the genome. This concept explains how altered expression of gene X can influence protein expression of gene Y, where X and Y are not necessarily located on the same 8

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Advances in Molecular Genetics chromosome. It underlies the basis of (genetic) pathway thinking and can be studied, for instance, by evaluating mRNA levels or alternative mRNA transcripts. The study from Wang et al. (2013) can serve as an example. As we have seen, miR-155 overexpression results in reduced SNX27 expression leading to neuronal degeneration. They identified the miR155-C/EBPß-SNX27 pathway as an important player in the neuropathogenesis of Down syndrome. Billingsley et al. (2013) demonstrated that 155 non-trisomic genes are differentially expressed in the mandible of the E13.5 Ts65Dn embryo (‘Down-mouse’). They showed that the presence of a trisomy can alter the expression of non-trisomic genes during development leading to structural changes associated with Down syndrome. By identifying genetic pathways that are disrupted by the presence of trisomy chromosome 21, more insight is gained into Down syndrome aetiology. This may finally serve as the basis for influencing or treating several Down syndrome manifestations (Billingsley et al. 2013). Chou et al. (2008) demonstrated that some euploid genes show a significant greater expression variance in human trisomy 21 tissues compared with controls. These studies demonstrate that the presence of trisomy chromosome 21 results in altered transcription on other genomic loci and provide the first evidence of the chromosome 21 interactome. It is likely that we will discover huge numbers of similar interactions between genes located at chromosome 21, or the proteins they encode for, and genes and proteins elsewhere in the genome explaining a significant part of the phenotype in Down syndrome. diSturbed chromoSome territorieS Chromosomes occupy specific, non-random regions within a nucleus, called chromosome territories. Cremer and Cremer (2010) have demonstrated (by using UV-microbeam experiments and later on FISH technique) that each chromosome has its own distinct ‘territory’ within the nucleus of cells. Chromosome territories are specific to cell and tissue type, and can even change during differentiation and development (Meaburn and Misteli 2007). The presence of an additional copy of chromosome 21 might cause a displacement of the other two chromosome 21s as well as other chromosomes from their normal sites. Finlan et al. (2008) demonstrated that expression or transcription of some (but not all) genes can be suppressed when chromosomes are relocated to the nuclear periphery. Therefore, it is easily conceivable that the presence of an extra chromosome 21 influences the ‘fixed’ chromosomal territory organization and, subsequently, alters expression of genes, including genes involved in the Down syndrome phenotype. These genes could be located on chromosome 21 or on other chromosomes displaced by the additional copy 21. We are unaware of studies of chromosome territories in individuals with Down syndrome or in other chromosome abnormalities. Genetic background as a phenotype contributor As well as the direct effects of an additional chromosome 21 the genetic background (all the other genes present, inherited from both parents) can influence the phenotype as well. The definition of genetic background is broad and undetermined but is likely to contribute to the Down syndrome phenotype and the huge variability observed among individuals with Down syndrome (Reeves et al. 2001). The genetic background is present anyway 9

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Down Syndrome: Current Perspectives and is not caused by the additional chromosome 21. Here, we discuss in short single nucleotide polymorphism (SNP) and copy number variations (CNVs) as part of this genetic background. Single nucleotide polymorphiSmS and copy number variationS on the background of triSomy 21 An SNP is a variation in the DNA sequence comprehending just one single nucleotide on a particular locus in the genome. SNPs between different members of biological species are common and usually do not cause disease. Genome-wide association studies (GWAS) can identify associations between particular SNPs and a disease, that is, some SNPs can occur more frequently in individuals with a particular disease. This variation itself does not cause the disease but is likely to contribute to the phenotype. Congenital heart defects (CHDs) occur in 40% of people with Down syndrome (Patterson 2009). Therefore, trisomy 21 increases the risk for CHD but it does not necessarily cause CHD: the genetic background has to play a role. Sailani et al. performed a GWAS study comparing a group with Down syndrome and CHD to a group with Down syndrome and no CHD. Two chromosome 21 risk alleles for CHD were identified and confirmed in a replication cohort (Sailani et al. 2013). A specific example of how polymorphisms may relate to phenotype comes from the work of Guéant et al. (2005). They investigated the influence of homocysteinaemia (t-Hcys), folate, vitamin B12 and related polymorphisms on intelligence quotient (IQ) in Down syndrome. They found an association between lower quotients and t-Hcys, carriers of the methylenetetrahydrofolate reductase 677 T allele and the transcobalamin 776 G allele. The association may be related to a defective methylation of homocysteine, affecting IQ (see more on methylation below). CNV describes the presence of an abnormal number of copies of one or more genome segments. This form of structural variation can involve relatively large segments of the genome (either deleted or duplicated). CNVs are relatively common but despite this their contribution and meaning often remain uncertain. Sailani et al. (2013) describe three CNV regions which seem to be associated with CHD in Down syndrome. When a gene is located within a particular CNV it can be an interesting candidate gene for further (functional) studies. Both SNPs and CNVs, therefore, may well be a component of the pathological genetic background of Down syndrome contributing to particular features of the phenotype. Key points • Trisomy for chromosome 21 produces the Down syndrome phenotype but the mechanism is unknown. • Gene overexpression and amplified developmental instability are likely to play a part. • Other genetic mechanisms including altered DNA methylation, an altered chromosome interactome and disturbed chromosome territories are all likely to contribute. • Molecular techniques currently available provide tools needed to clarify these biological processes. 10

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Advances in Molecular Genetics • Understanding the phenotype pathogenesis is essential to developing management strategies, which can improve health and quality of life for individuals with Down syndrome and their families. REFERENCES Adorno M, Sikandar S, Mitra SS et al. (2013) Usp16 contributes to somatic stem-cell defects in Down’s syndrome. Nature 501: 380–384. doi: 10.1038/nature12530. Epub 11 September 2013. Aït Yahya-Graison E, Aubert J, Dauphinot L et al. (2007) Classification of human chromosome 21 geneexpression variations in Down syndrome: Impact on disease phenotypes. Am J Hum Genet 81: 475–491. Billingsley CN, Allen JR, Baumann DD et al. (2013) Non-trisomic homeobox gene expression during craniofacial development in the Ts65Dn mouse model of Down syndrome. Am J Med Genet 161A: 1866–1874. doi: 10.1002/ajmg.a.36006. Chango A, Abdennebi-Najar L, Tessier F et al. (2006) Quantitative methylation-sensitive arbitrarily primed PCR method to determine differential genomic DNA methylation in Down Syndrome. Biochem Biophys Res Commun 349: 492–496. Chou CY, Liu LY, Chen CY et al. (2008) Gene expression variation increase in trisomy 21 tissues. Mamm Genome 19: 398–405. doi: 10.1007/s00335-008-9121-1. Cremer T, Cremer M (2010) Chromosome territories. Cold Spring Harb Perspect Biol 2: a003889. doi: 10.1101/cshperspect.a003889. Dominguez D, Tournoy J, Hartmann D et al. (2005) Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280: 30797–30806. Finlan LE, Sproul D, Thomson I et al. (2008) Recruitment to the nuclear periphery can alter expression of genes in human cells. PLOS Genet 4: e.1000039. doi: 10.1371/journal.pgen.1000039. Guéant J-L, Anello G, Bosco P et al. (2005) Homocysteine and related genetic polymorphisms in Down’s syndrome IQ. J Neurol Neurosurg Psychiatry 76: 706–709. doi: 10.1136/jnnp.2004.039875. Harper P (2006) First Years of Human Chromosomes – The Beginnings of Human Cytogenetics. Oxford shire: Scion Publishing Ltd. Kahlem P (2006) Gene-dosage effect on chromosome 21 transcriptome in trisomy 21: Implication in Down syndrome cognitive disorders. Behav Genet 36: 416–428. Kerkel K, Schupf N, Hatta K et al. (2010) Altered DNA methylation in leukocytes with trisomy 21. PLOS Genet 6. doi: 10.1371/journal.pgen.1001212. Korbel JO, Tirosh-Wagner T, Urban AE et al. (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci USA 106: 12031– 12036. doi: 10.1073/pnas.0813248106. Korenberg JR, Kawashima H, Pulst SM et al. (1990) Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 47: 236–246. Lejeune J, Gauthier M, Turpin R (1959) Etudes des chromosomes somatiques de neuf enfants mongoliens. C R Acad Sci 248: 1721–1722. Letourneau A, Antonarakis SE (2012) Genomic determinants in the phenotypic variability of Down syndrome. Prog Brain Res 197: 15–28. doi: 10.1016/B978-0-444-54299-1.00002-9. Li CM, Guo M, Salas M et al. (2006) Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21. BMC Med Genet 24: 1–15. doi: 10.1186/1471-2350-7-24. Lockstone HE, Harris LW, Swatton JE, Wayland MT, Holland AJ, Bahn S (2007) Gene expression profiling in the adult Down syndrome brain. Genomics 90: 647–660. Mao R, Zielke CL, Zielke HR, Pevsner J (2003) Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81: 457–467. Meaburn KJ, Misteli T (2007) Cell biology: Chromosome territories. Nature 445: 379–381. Nadel L (2003) Down’s syndrome: A genetic disorder in biobehavioral perspective. Genes Brain Behav 2: 156–166. Olson LE, Roper RJ, Sengstaken CL et al. (2007) Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet 16: 774–782. Oyama F, Cairns NJ, Shimada H, Oyama R, Titani K, Ihara Y (1994) Down’s syndrome: Up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem 62: 1062–1066.

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Down Syndrome: Current Perspectives Patterson D (2007) Genetic mechanisms involved in the phenotype of Down syndrome. Ment Retard Dev Disabil Res Rev. 13: 199–206. Patterson D (2009) Molecular genetic analysis of Down syndrome. Hum Genet 126: 195–214. doi: 10.1007/ s00439-009-0696-8. Prandini P, Deutsch S, Lyle R et al. (2007) Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet 81: 252–263. Rachidi M, Lopes C (2010) Molecular and cellular mechanisms elucidating neurocognitive basis of functional impairments associated with intellectual disability in Down syndrome. Am Assoc Intellect Dev Disabil 115: 83–112. doi: 10.1352/1944-7558-115.2.83. Reeves RH, Baxter LL, Richtsmeier JT (2001) Too much of a good thing: Mechanisms of gene action in Down syndrome. Trends Genet 17: 83–88. Rovelet-Lecrux A, Hannequin D, Raux G et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38: 24–26. Sailani MR, Makrythanasis P, Valsesia A et al. (2013) The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Res 23: 1410–1421. doi: 10.1101/gr.147991.112. Salehi A, Delcroix JD, Belichenko PV et al. (2006) Increased APP expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51: 29–42. Shapiro BL (1983) Down syndrome – A disruption of homeostasis. Am J Med 14: 241–269. Turek-Plewa J, Jagodziński PP (2005) The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett 10: 631–647. Wang X, Zhao Y, Zhang X et al. (2013) Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down’s syndrome. Nat Med 19: 473–480. doi: 10.1038/nm.3117. Webb RL, Murphy MP (2012) b-Secretases, Alzheimer’s disease, and Down syndrome. Curr Gerontol Geriatr Res 2012: 362839. doi: 10.1155/2012/362839. Zigman WB, Devenny DA, Krinsky-McHale SJ et al. (2008) Alzheimer’s disease in adults with Down syndrome. Int Rev Res Ment Retard 36: 103–145.

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3 ANTENATAL DIAGNOSIS: GIVING THE NEWS Shiela Puri and Joan Morris

Introduction During pregnancy, women are offered tests screening for a number of different conditions known to have an impact on a child’s health and development. At the initial consultation, the midwife or doctor explains the purpose of screening and potential outcomes of the conditions involved and provides written information on the tests involved. Parents often only wish to proceed with screening tests after they have learnt more about the conditions and the potential impact the conditions may have on their family. Screening tests can create anxiety, particularly as results and their implications can be uncertain. It is therefore imperative that the professional involved at each stage of the process imparts information in a sensitive, non-judgemental fashion and is knowledgeable regarding the condition screened. The focus of this chapter is the current approach to antenatal screening for Down syndrome. A case scenario is used to illustrate parental perspectives during each stage of the process. Who is offered antenatal tests for Down syndrome? In 1933, Penrose identified that older women were at an increased chance of having a baby with Down syndrome (Penrose 1933, 2009). Figure 3.1 shows how the chance increases with maternal age. The chance increases from less than 1 per 1000 for women under 30, to 4 per 1000 in women aged 35 and over, to 11 per 1000 in women aged 40. In the past as only invasive testing (amniocentesis) was available, only women who were at high risk (i.e. over 35 years old) were offered testing. Since the advent of non-invasive screening tests in England, screening is offered to all pregnant women irrespective of their age. What tests are currently offered for the antenatal diagnosis of Down syndrome? Two types of antenatal tests are available, screening tests and diagnostic tests. Initially noninvasive screening tests that carry no risk to the mother or fetus are offered to determine the probability of the baby having Down syndrome. If the screening tests suggest a high probability, diagnostic tests are offered; these are currently invasive and carry a 0.5–1% risk of miscarriage. The initial screening involves taking a maternal blood sample to measure serum markers and a fetal ultrasound scan to determine nuchal translucency thickness and any other 13

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Down Syndrome: Current Perspectives

Prevalence of Down syndrome per 1000 live births

50

40

30

20

10

0 20

25

30

35

40

45

50

Maternal age at birth (years)

Fig. 3.1. Chance of having a baby with Down syndrome according to maternal age.

anatomical abnormalities. The probability of having a baby with Down syndrome is calculated by combining the maternal age and the results of the ultrasound findings and serum markers (Wald et al. 2003, 2004). As these markers all change during the stages of pregnancy, an initial fetal dating scan improves the accuracy of the results. Does a previous pregnancy with Down syndrome increase the chance of having another baby with Down syndrome? Women who have had a previous pregnancy with Down syndrome have an increased chance of having another baby with Down syndrome subsequently, this is dependent on the age of the woman at her first pregnancy. For example, if her first affected pregnancy occurred when she was 20 years old she will have an excess chance of 6.4 per 1000 above her age related chance for all subsequent pregnancies, whereas if her first affected pregnancy occurred when she was 40 years old, the excess chance is only 0.4 per 1000. In the UK women are advised to have initial screening tests rather than to proceed straight to a diagnostic test in subsequent pregnancies. What information is available to give women regarding screening tests? Case Scenario Zeneb is a 33-year-old Sudanese asylum seeker, residing in the UK for 2 years. She is expecting her first child and attends her first antenatal consultation at 10 weeks’ gestation with her midwife. She mainly speaks Arabic. 14

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Antenatal Diagnosis: Giving the News In the UK, women are offered a booklet ‘Screening tests for you and your baby’ (see Resources at the end of the chapter and Table 3.1 below). This covers all aspects of screening during pregnancy and the first few days after birth. Versions are available in 19 different languages including a video in British Sign Language. What considerations need to be taken at the time of discussing screening tests With zeneb? Is Zeneb able to understand English adequately? Is Zeneb able to understand the concept of screening tests and their implications? Are there any cultural and religious considerations? Does Zeneb have access to any social support within the community to discuss her concerns? In this case scenario, it is important for an Arabic interpreter to be available for all consultations, including when the screening ultrasound is performed. Zeneb should be strongly encouraged to attend all appointments with her partner or someone who can provide her with support at the time of the consultations. The professionals need to allow

TABLE 3.1 Overview of antenatal screening tests for Down syndrome Screening test and timing of test during pregnancy

Test performed

Predictive value of the test

Integrated test 10 to 13 wks’ gestation

Ultrasound measurement of nuchal translucency thickness (11 wks + 2 d to 14 wks +1 d) and maternal blood test PAPP-A, AFP, hCG, uE3, inhibin

90% detection rate for 1.3% false-positive rate

Combined test 10 to 14 wks’ gestation

Ultrasound measurement of nuchal translucency thickness (11 wks + 2 d to 14 wks + 1 d) and maternal blood test (10–14 wks) plasma protein-A and free ß-human chorionic gonadotrophin

84% detection rate for 2.2% false-positive rate (1 in 150 cut-off)

Quad test 14 to 20 wks’ gestation

Maternal blood test: alphafetoprotein, total human chorionic gonadotrophin, unconjugated oestriol, inhibin

80% detection rate for 3.5% false-positive rate (1 in 150 cut-off)

Cell-free fetal DNA 10 wks’ gestation onwards (not routinely available 2013)

Maternal blood test karyotyping after sequencing fetal DNA in maternal blood

>98% for 0.2% false-positive rate, test failure rate is about 4%

AFP, alpha-fetoprotein; cff, cell-free fetal; free ß-hCG, free ß-human chorionic gonadotrophin; hCG, human chorionic gonadotrophin; inhibin, inhibin-A; PAPP-A, plasma protein-A; uE3, unconjugated oestriol.

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Down Syndrome: Current Perspectives themselves adequate time during the consultation to ensure that Zeneb understands the purpose and implications of screening and has an opportunity to ask questions to clarify what is involved at each stage. Anecdotally, parents have often stated that it is difficult to understand the concept of statistics of chance and probability. Visual aids can help. It is worth asking parents what they have understood. What considerations need to be taken at the time of the screening ultrasound? Zeneb attends for her screening ultrasound scan at 13 weeks; the findings showed an increased nuchal translucency thickness. An interpreter needs to be present for all these consultations and procedures. The ultrasonographer must be trained on how to discuss results with the mother in a sensitive manner and that a senior colleague should be called to discuss results. It is important that the news is imparted to Zeneb whilst she is being supported by her partner or person of her choice. The suspected diagnosis should be given to the mother by a health professional knowledgeable about the local process and pathways for further diagnostic testing for Down syndrome. This should be done in a quiet, private environment and face-to-face with adequate time being set aside. Zeneb should be offered an appointment within 3 working days to discuss the probability of having a baby with Down syndrome and implications of invasive diagnostic testing. This should be clearly explained in a non-judgemental manner. If Zeneb decides to proceed to invasive diagnostic testing, it must be made clear how and when the results will be delivered to her. What are the currently available antenatal diagnostic tests for Down syndrome? Currently, a definitive antenatal diagnosis of Down syndrome is made by identifying the presence of an extra chromosome 21 in fetal cells obtained from the placenta, chorionic villous sampling or in a sample of amniotic fluid obtained by amniocentesis. Chorionic villous sampling can be carried out between 11 and 14 weeks’ gestation, whilst amniocentesis is only possible, technically after 15 weeks’ gestation. Chorionic villous sampling carries a slightly higher risk of miscarriage; however, it enables an earlier diagnosis. Current UK guidelines recommend that the screening for Down syndrome, and the consequent decision on whether to proceed with invasive diagnostic testing, should be performed before 14 completed weeks’ gestation. Are there non-invasive techniques to diagnose Down syndrome antenatally? In 1997, cell-free fetal (CFF) DNA and RNA were discovered in maternal blood from 5 weeks’ gestation. This offered the first opportunity for a non-invasive technique to identify prenatal genetic markers. A peripheral maternal blood sample with circulating free fetal DNA allows fetal karyotyping to be undertaken and hence the possibility of confirming the 16

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Antenatal Diagnosis: Giving the News diagnosis (Sifakis et al. 2012). Currently, there are limitations to this procedure; the advice in 2013 is that a positive CFF karyotyping result must be confirmed by chorionic villous sampling or amniocentesis (Benn et al. 2013). It is anticipated that in the future non-invasive antenatal diagnosis will replace the current invasive techniques of amniocentesis and chorionic villous sampling for the definitive diagnosis of aneuploidies. What are the limitations of non-invasive testing? The quantity of CFF DNA in maternal blood is extremely small and constitutes only 3–10% of maternal blood. Chromosome 21 is one of the smallest chromosomes and accounts for only 3% of all genetic material. To increase the sensitivity, computer-intensive methods, called massively parallel sequencing (MPS) methods, have been developed to distinguish between two copies of maternal chromosome 21 and three copies in the fetal DNA. There are practical limitations to using the test for diagnostic purposes. The test failure rates, though not fully established, are considered to be about 4%, as the testing so far has been primarily undertaken in pregnancies where there has been a higher chance of Down syndrome and not in the general population. There is insufficient information on the accuracy of the tests in multiple gestation pregnancies or where there is an early death of a co-twin (Canick et al. 2012). The presence of placental mosaicism may also result in an incorrect diagnosis. What are the implications of non-invasive prenatal testing? Ethical concerns have been raised around non-invasive prenatal testing with implications of reemergence of the concept of eugenics and the burden on the woman on decision making. Natoli et al. (2012) in their systematic review of prenatal diagnosis of Down syndrome and termination rates showed evidence of a temporal reduction of termination rates in the presence of increased uptake of prenatal testing and diagnosis. They attributed this to better access to health and social care for people with Down syndrome. This is in contrast to the earlier reviews by Mansfield et al. (1999). However, Bryant (2014) emphasizes the importance of the possible psychosocial impact of non-invasive prenatal testing and the importance for the health care professional to be trained in supporting women in making difficult decision making and maintaining neutrality. Training is available to all health professionals in the UK around counselling and life with Down syndrome through the Down’s Syndrome Association, ‘Tell it right, Start it right’ (2014). What is the population impact of antenatal testing? In 1989, the National Down syndrome Cytogenetic Register began collecting information on all prenatal and postnatal diagnoses of Down syndrome in England and Wales. The top line in Figure 3.2 shows how the prevalence of Down syndrome has increased over time, mainly due to the increases in maternal age that have occurred over this time. The lower line shows how the birth prevalence of Down syndrome has remained fairly constant over the past 20 years. The difference between the two lines is due to the majority of prenatal 17

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Down Syndrome: Current Perspectives 3

All diagnoses

Prevalence per 1000 live births

2.5 2

1.5 1 Live births 0.5 0 1990

1995

2000 Year of diagnosis

2005

2010

Fig. 3.2. Prevalence of diagnoses of Down syndrome and live births with Down syndrome per 1000 births in England and Wales.

diagnoses resulting in a termination and in addition a small proportion resulting in a miscarriage. A prevalence of 1 per 1000 is equivalent to 700 Down syndrome births per year. Figure 3.3 shows how the proportion of prenatal diagnoses has increased over time, with the increases being greatest amongst women under 35 years of age. At a given cut-off level, the detection rate (and false-positive rate) is higher among older women and therefore screening tests are more sensitive for older women. This would explain why the proportion of Down syndrome pregnancies detected prenatally is higher for older mothers than younger mothers; a lower uptake of screening in younger women has not been observed and could not account for the magnitude of the difference in proportions. With the advent of more effective screening tests, the gap in proportions of Down syndrome pregnancies detected prenatally in older and younger mothers is expected to decrease even further. What considerations need to be taken at the time of discussing the results? Zeneb has an amniocentesis at 16 weeks’ gestation and the results confirm that the baby has Down syndrome. Even though Zeneb’s midwife had taken the time to explain the tests through an Arabic interpreter, the emotional impact of receiving the diagnosis of Down syndrome in her 18

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Antenatal Diagnosis: Giving the News

Percentage diagnosed prenatally

80

60

40

20

0 1990

1995

2000 Year of diagnosis

2005

2010

Fig. 3.3. Percentage of Newborns with Down syndrome following prenatal diagnosis according to maternal age and year of diagnosis.

unborn child can be considerable and can cause distress. The shock of any prenatal fetal abnormality makes it hard for women to take in any information, even if they are well informed prior to the testing. It is important to give parents time to understand the information, prior to making potentially life-changing decisions. It is essential to have a well-planned and coordinated pathway in place to give the diagnosis. Professionals should be trained in giving difficult information to families, be aware of their own personal views and be non-judgemental and sensitive. The diagnosis must be given in a face-to-face consultation in a supportive environment. It is important for the information to be imparted in a sympathetic and factual manner; it must not be considered as ‘bad news’. In some units, this is done jointly by the fetal medicine team including genetic counsellors with a good knowledge of the long-term outcomes. What are the considerations to enable the pregnancy and delivery of the baby to be a positive experience for the family? Zeneb and her partner decide to continue with the pregnancy. Zeneb should be supported in her decision. It is helpful to give her the contact details of the Down Syndrome Association and the local parent support group. The booklet ‘Continuing Pregnancy with a Diagnosis of Down’s syndrome’ (see Resources at end of chapter) is a useful resource. 19

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Down Syndrome: Current Perspectives It is important to ensure that the woman’s needs are met in the same way as those of a typical expectant mother so that she is not excluded from universally available services. Extra effort should also be made to adapt the services to the individual as appropriate. Once the diagnosis is confirmed, a detailed fetal anomaly scan must be organized. The birth of the baby may need to be planned in a specialized unit with immediate access to specialist services, for example, paediatric surgery or cardiology. The care should be well coordinated with easy access to named health professionals throughout the pregnancy. This role is usually taken on by either the midwife or the genetic counsellor. What considerations should be made at the time of the birth of the baby? Zeneb gives birth to a baby boy, Talat, at 37 weeks’ gestation, weighing 2.8 kg. As Zeneb and her partner were aware antenatally of the diagnosis of Down syndrome, every effort should be made by the midwife and obstetrician involved in her care to have a one-to-one discussion soon after birth. The parents should be congratulated on the birth of their baby boy. Staff should make every effort to approach mother and baby with sensitivity so that they are not made to feel different. It is helpful to offer Zeneb the option of the privacy of staying in a side room if medically appropriate and allowing her partner to stay with her for support, thus enabling both parents to bond with their baby. The diagnosis of Down syndrome should be given by a professional knowledgeable in Down syndrome with an understanding of the health and educational outcomes for people with Down syndrome, as outcomes have improved considerably over the last 25 years (Zhu et al. 2013). Many young people with Down syndrome are able to contribute positively to society. A detailed account on the principles of imparting the diagnosis to parents after the birth of their child with Down syndrome is discussed in detail in Chapter 4. Kathryn and John are parents to Sophie aged 6, with a diagnosis of Down syndrome, and her older sister aged 8. They kindly agreed to share an account of their experiences and want to emphasize the importance of professionals getting it right, from the start when sharing the diagnosis of Down syndrome with parents. ‘I was told there were some complications during my scan, when I was on my own. John had popped out of the room for a few minutes, and he had made everyone aware it would only be a few minutes. He returned to a devastated wife. I still get incredibly upset talking about the scan and that experience and do not understand why I was told when I was on my own. It is so important, if possible, to have support when receiving unexpected news. Following further testing I was called by a doctor at the hospital who told me it was Down syndrome. I was 5 months pregnant at this time. The conversation started with, “I’m sorry, but it’s bad news. . .”. That phone call was so important to me and to hear my baby referred to as “bad news” 20

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Antenatal Diagnosis: Giving the News was devastating. Now 5 years on, and since Sophie’s birth, I know it is not bad news. I was then asked what I wanted to do. I asked about meeting with a Genetic Counsellor. I was put in touch with one immediately. She was a wonderful support to us all and was always available if needed. The Genetic Counsellor support was not offered but was available when I asked. It would be good if it was offered routinely. After the antenatal diagnosis was established, the care given was very positive. On having Sophie, I was taken to the transitional care ward and John was immediately told he could not stay. Why? I had just given birth. I was left alone with my new baby, no support was offered. While on the Transitional ward, both the Consultant who was there at the original scan and the Paediatrician visited us, this meant a lot to us. Our experience of the antenatal diagnosis sounds negative, but it is such an important time for parents and how the news is delivered is vital. Making a decision following the diagnosis is of course a personal one; however I feel from my experience, it is so important to have information in order to make an informed decision’. Key points • In the UK, pregnant women are offered initial screening tests for Down syndrome. • If indicated, subsequent diagnostic testing is offered. • Diagnostic tests involve an invasive procedure with a small risk of a miscarriage. • In the future, non-invasive diagnostic tests will be available. • It is imperative that professionals involved in the screening and diagnostic process are trained to share information in a sensitive and non-judgemental manner. • Information should be given to parents in an easily understood way, and they should be given the opportunity to ask questions. • Parents who wish to proceed for diagnostic testing to prepare themselves psychologically for their baby’s birth rather than for the purpose of termination should be supported in their decisions throughout the pregnancy and birth. • Every effort should be made to ensure that the woman is supported by her partner at the time of imparting the suspected/definitive diagnosis. • It is helpful to offer the family support from the local parents Down syndrome support group and the Down Syndrome Association. REFERENCES Benn P, Borell A, Chiu R et al. (2013) Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 33: 622–629. doi: 10.1002/pd.4139. Epub 21 May 2013. Bryant L (2014) Non-invasive prenatal testing for Down’s syndrome: Psychologically speaking, what else do we need to know? J Reprod Infant Psychol 32: 1–4. doi: 10.1080/02646838.2014.874115. Canick JA, Kloza EM, Lambert-Messerlian GM et al. (2012) DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn 32: 730–734. doi: 10.1002/ pd.3892. Epub 14 May 2012. Mansfield C, Hopfer S, Marteau TM (1999) Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: A systematic literature review. European

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Down Syndrome: Current Perspectives Concerted Action: DADA (Decision-making After the Diagnosis of a fetal Abnormality). Prenat Diagn 19: 808–812. doi: 10.1002/(SICI)1097-0223(199909)19:918 y

Free T4 (pmol/L)

Total T4 (nmol/L)

Free T3 (pmol/L)

Total T3 (pmol/L)

TSH (mU/L)

TPO-ab (IU/mL)

TSHR-ab (u/L)

8.5–30.5

80–160

4.5–10

1.5–3.4

1.3–16